The biguanide metformin, an effective first-line agent for the treatment of type 2 diabetes, has come a long way from the days when the FDA hesitated to approve the drug due to risk for lactic acidosis. Today, metformin, now an inexpensive generic and widely available, has garnered a new reputation as a possible anti-aging wonder pill that influences a host of metabolic and cellular processes closely associated with the development of age-related conditions.

Kishore Gadde

“The story of metformin just keeps getting bigger,” Kishore Gadde, MD, the Fairfax Foster Bailey endowed chair in heart disease prevention and medical director of clinical services at Pennington Biomedical Research Center at Louisiana State University, told Endocrine Today.“The growing interest now — especially in the last 5 years — has been about metformin’s effects that are independent of glucose lowering. There may be effects on inflammation and oxidative stress, for example, which could explain a lot of things. If you reduce chronic damage that results from inflammation, that could have benefits for aging, for cardiovascular disease, for cancer.”

Small cell and animal studies have yielded exciting findings related to metformin and age-related diseases, with some suggesting that metformin may delay the aging process and have a neuroprotective role.

First aging studies

Despite promising findings in multiple animal models, progress for human research using randomized controlled trials to evaluate metformin’s clinical impact is just beginning.

Nir Barzilai

Nir Barzilai, MD, an endocrinologist and director of the Institute for Aging Research at the Albert Einstein College of Medicine, said he and colleagues plan to begin recruiting participants for a metformin trial in humans later this year, funded by the American Federation for Aging Research. That study, Targeting Aging with Metformin (TAME) is designed to demonstrate metformin’s ability to delay the onset of comorbidities related to aging, thereby reducing the period of morbidity at the end of life. Researchers plan to recruit 3,000 older adults (aged 65-79 years) without diabetes who will be randomly assigned to 1,500 mg metformin daily or placebo for 4 years. The primary endpoint will be any one of a range of the age-related conditions myocardial infarction, heart failure, stroke, most cancers, dementia and death.

“My interest is not to prove that metformin delays aging,” Barzilai told Endocrine Today. “We know that we can target aging with a variety of drugs, some in humans. Rapamycin extends life span in mice by 24%, even by 10% at end of life. This is not about life span. This is about health span.”

If metformin can target and delay aging, Barzilai said, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.

In February, researchers began recruiting for the Veterans Affairs’ Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes (VA-IMPACT), a placebo-controlled study of 7,868 older adults with atherosclerotic CVD and prediabetes. The primary outcomes for VA-IMPACT are time to death from any cause, MI, stroke, hospitalization for unstable angina or symptom-driven coronary revascularization. The study’s estimated completion date is August 2024.

A smaller metformin study is already underway at University of Texas Health Science Center in San Antonio to assess the drug’s possible benefits on frailty in older adults, Gadde said. The study, sponsored by the National Institute on Aging, includes 120 older adults (aged at least 65 years) with prediabetes randomly assigned to metformin (titrated up to 1,000 mg twice daily) or placebo, and has an estimated completion date of October 2022.

“The real risk for diabetes is aging,” Barzilai said. “Aging is a 1,000-fold risk while obesity is an eightfold risk. There is no comparison. From my point of view, if you have any improvement in one disease, you’re just exchanging one disease for another, unless you target aging. Aging is a target for diabetes just as much as specific drugs are.”

The biguanide metformin, an effective first-line agent for the treatment of type 2 diabetes, has come a long way from the days when the FDA hesitated to approve the drug due to risk for lactic acidosis.

Source: Adobe Stock

Possible mechanisms

There are several possible mechanisms to explain metformin’s putative benefits on aging, Gadde said. According to researchers, metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, and reduces inflammation through the suppression of NF-kB via AMPK-dependent pathways. Metformin may also ameliorate DNA and cellular damage by decreasing reactive oxygen species synthesis through reverse electron flux, Gadde said, and by inhibiting mechanistic target of rapamycin (mTOR) pathways, thus reducing oxidative stress.

“Additionally, metformin may limit the negative effects of ceramides, thereby preventing myoblast senescence and improving overall tissue health,” said Gadde, who recently led a study on metformin for long-term weight maintenance.

In an analysis of 365 adults aged at least 55 years participating in the Singapore Longitudinal Ageing Studies (SLAS), Tze Pin Ng, MD, MBBS, a physician epidemiologist and public health medicine specialist with the gerontological research program at the National University of Singapore, and colleagues assessed the association of metformin use vs. nonuse with cognitive impairment (determined by Mini-Mental State Examination score) and stratified by duration of use (6 years, n = 114; > 6 years, n = 90). The results, published in the January 2014 issue of Journal of Alzheimer’s Disease, showed that metformin use was inversely associated with cognitive impairment in longitudinal analysis (OR = 0.49; 95% CI, 0.25-0.95) and that the lowest risk for cognitive impairment was associated with use of the drug for more than 6 years in cross-sectional analysis (OR = 0.3; 95% CI, 0.11-0.8) and longitudinal analysis (OR = 0.27; 95% CI, 0.12-0.6).

In a November 2014 observational study published in Diabetes, Obesity and Metabolism, Christian A. Bannister, PhD, MSc, a data scientist with the Cochrane Institute of Primary Care and Public Health at Cardiff University, U.K., studied the progression to all-cause mortality among 78,241 patients with type 2 diabetes treated with metformin, 12,222 treated with sulfonylureas and 90,463 controls without diabetes, using data from the U.K. Clinical Practice Research Datalink.

“This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in nondiabetes,” the researchers wrote.

Reducing dementia risk

In a study published in Annals of Family Medicine in July, researchers found that African Americans within the VA health system who were older than 50 years and treated with metformin for diabetes had a much lower risk for dementia vs. similar patients treated with sulfonylureas.

Jeffrey F. Scherrer, PhD, associate professor and research director of the department of family and community medicine at the Saint Louis University School of Medicine, and colleagues reviewed medical records of 73,761 patients — 10,559 of whom were African American — treated at VA hospitals from 2000 to 2015 who had not received diabetes medications or a dementia diagnosis before fiscal year 2002.

Researchers found that metformin use was associated with a lower risk for dementia vs. sulfonylureas among African American patients (HR = 0.73; 95% CI, 0.6-0.89), but not white patients (HR = 0.96; 95% CI, 0.9-1.03). The strongest association was found in African American patients aged 50 to 64 years (HR = 0.6; 95% CI, 0.45-0.81). In patients aged 65 to 74 years, metformin was significantly associated with lower risk for dementia in both groups. No such association was found in patients older than 75 years.

“The protective effects of metformin might be observed in younger patients not included in existing research,” Scherrer and colleagues wrote.

But while the potential promise of metformin is exciting to researchers, Gadde said, it will be years before there is empirical data to support anti-aging claims.

“Without clearly knowing, if you ask most scientists, they would not encourage people just going and taking metformin,” Gadde said. “That said, people who are aged 70-plus years, are they going to wait 15 years for firm data on metformin? Whenever there is potentially exciting, emerging data, people want to jump in. But there can be risks if you don’t completely know what you are getting into.”

Barzilai, who called metformin a “tool” to open the door for aging-related FDA indications, said TAME and studies like it are going to change the way researchers look at some commonly used drugs.

“If you ask people to point out who around them may be aged 60 years or older, they’ll do a pretty good job,” Barzilai said. “Everyone knows there is a biology of aging. For some reason, they think they can’t do anything about it. That is a mistake. You can intervene in aging, even late in aging. Our lives are going to change when we have the regulatory pathway to do that.” – by Regina Schaffer

The biguanide metformin, an effective first-line agent for the treatment of type 2 diabetes, has come a long way from the days when the FDA hesitated to approve the drug due to risk for lactic acidosis. Today, metformin, now an inexpensive generic and widely available, has garnered a new reputation as a possible anti-aging wonder pill that influences a host of metabolic and cellular processes closely associated with the development of age-related conditions.

Kishore Gadde

“The story of metformin just keeps getting bigger,” Kishore Gadde, MD, the Fairfax Foster Bailey endowed chair in heart disease prevention and medical director of clinical services at Pennington Biomedical Research Center at Louisiana State University, told Endocrine Today.“The growing interest now — especially in the last 5 years — has been about metformin’s effects that are independent of glucose lowering. There may be effects on inflammation and oxidative stress, for example, which could explain a lot of things. If you reduce chronic damage that results from inflammation, that could have benefits for aging, for cardiovascular disease, for cancer.”

Small cell and animal studies have yielded exciting findings related to metformin and age-related diseases, with some suggesting that metformin may delay the aging process and have a neuroprotective role.

First aging studies

Despite promising findings in multiple animal models, progress for human research using randomized controlled trials to evaluate metformin’s clinical impact is just beginning.

Nir Barzilai

Nir Barzilai, MD, an endocrinologist and director of the Institute for Aging Research at the Albert Einstein College of Medicine, said he and colleagues plan to begin recruiting participants for a metformin trial in humans later this year, funded by the American Federation for Aging Research. That study, Targeting Aging with Metformin (TAME) is designed to demonstrate metformin’s ability to delay the onset of comorbidities related to aging, thereby reducing the period of morbidity at the end of life. Researchers plan to recruit 3,000 older adults (aged 65-79 years) without diabetes who will be randomly assigned to 1,500 mg metformin daily or placebo for 4 years. The primary endpoint will be any one of a range of the age-related conditions myocardial infarction, heart failure, stroke, most cancers, dementia and death.

“My interest is not to prove that metformin delays aging,” Barzilai told Endocrine Today. “We know that we can target aging with a variety of drugs, some in humans. Rapamycin extends life span in mice by 24%, even by 10% at end of life. This is not about life span. This is about health span.”

PAGE BREAK

If metformin can target and delay aging, Barzilai said, its administration should be associated with fewer age-related diseases in general, rather than merely the decreased incidence of a single disease.

In February, researchers began recruiting for the Veterans Affairs’ Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes (VA-IMPACT), a placebo-controlled study of 7,868 older adults with atherosclerotic CVD and prediabetes. The primary outcomes for VA-IMPACT are time to death from any cause, MI, stroke, hospitalization for unstable angina or symptom-driven coronary revascularization. The study’s estimated completion date is August 2024.

A smaller metformin study is already underway at University of Texas Health Science Center in San Antonio to assess the drug’s possible benefits on frailty in older adults, Gadde said. The study, sponsored by the National Institute on Aging, includes 120 older adults (aged at least 65 years) with prediabetes randomly assigned to metformin (titrated up to 1,000 mg twice daily) or placebo, and has an estimated completion date of October 2022.

“The real risk for diabetes is aging,” Barzilai said. “Aging is a 1,000-fold risk while obesity is an eightfold risk. There is no comparison. From my point of view, if you have any improvement in one disease, you’re just exchanging one disease for another, unless you target aging. Aging is a target for diabetes just as much as specific drugs are.”

The biguanide metformin, an effective first-line agent for the treatment of type 2 diabetes, has come a long way from the days when the FDA hesitated to approve the drug due to risk for lactic acidosis.

Source: Adobe Stock

Possible mechanisms

There are several possible mechanisms to explain metformin’s putative benefits on aging, Gadde said. According to researchers, metformin activates AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, and reduces inflammation through the suppression of NF-kB via AMPK-dependent pathways. Metformin may also ameliorate DNA and cellular damage by decreasing reactive oxygen species synthesis through reverse electron flux, Gadde said, and by inhibiting mechanistic target of rapamycin (mTOR) pathways, thus reducing oxidative stress.

“Additionally, metformin may limit the negative effects of ceramides, thereby preventing myoblast senescence and improving overall tissue health,” said Gadde, who recently led a study on metformin for long-term weight maintenance.

In an analysis of 365 adults aged at least 55 years participating in the Singapore Longitudinal Ageing Studies (SLAS), Tze Pin Ng, MD, MBBS, a physician epidemiologist and public health medicine specialist with the gerontological research program at the National University of Singapore, and colleagues assessed the association of metformin use vs. nonuse with cognitive impairment (determined by Mini-Mental State Examination score) and stratified by duration of use (6 years, n = 114; > 6 years, n = 90). The results, published in the January 2014 issue of Journal of Alzheimer’s Disease, showed that metformin use was inversely associated with cognitive impairment in longitudinal analysis (OR = 0.49; 95% CI, 0.25-0.95) and that the lowest risk for cognitive impairment was associated with use of the drug for more than 6 years in cross-sectional analysis (OR = 0.3; 95% CI, 0.11-0.8) and longitudinal analysis (OR = 0.27; 95% CI, 0.12-0.6).

PAGE BREAK

In a November 2014 observational study published in Diabetes, Obesity and Metabolism, Christian A. Bannister, PhD, MSc, a data scientist with the Cochrane Institute of Primary Care and Public Health at Cardiff University, U.K., studied the progression to all-cause mortality among 78,241 patients with type 2 diabetes treated with metformin, 12,222 treated with sulfonylureas and 90,463 controls without diabetes, using data from the U.K. Clinical Practice Research Datalink.

“This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in nondiabetes,” the researchers wrote.

Reducing dementia risk

In a study published in Annals of Family Medicine in July, researchers found that African Americans within the VA health system who were older than 50 years and treated with metformin for diabetes had a much lower risk for dementia vs. similar patients treated with sulfonylureas.

Jeffrey F. Scherrer, PhD, associate professor and research director of the department of family and community medicine at the Saint Louis University School of Medicine, and colleagues reviewed medical records of 73,761 patients — 10,559 of whom were African American — treated at VA hospitals from 2000 to 2015 who had not received diabetes medications or a dementia diagnosis before fiscal year 2002.

Researchers found that metformin use was associated with a lower risk for dementia vs. sulfonylureas among African American patients (HR = 0.73; 95% CI, 0.6-0.89), but not white patients (HR = 0.96; 95% CI, 0.9-1.03). The strongest association was found in African American patients aged 50 to 64 years (HR = 0.6; 95% CI, 0.45-0.81). In patients aged 65 to 74 years, metformin was significantly associated with lower risk for dementia in both groups. No such association was found in patients older than 75 years.

“The protective effects of metformin might be observed in younger patients not included in existing research,” Scherrer and colleagues wrote.

But while the potential promise of metformin is exciting to researchers, Gadde said, it will be years before there is empirical data to support anti-aging claims.

“Without clearly knowing, if you ask most scientists, they would not encourage people just going and taking metformin,” Gadde said. “That said, people who are aged 70-plus years, are they going to wait 15 years for firm data on metformin? Whenever there is potentially exciting, emerging data, people want to jump in. But there can be risks if you don’t completely know what you are getting into.”

PAGE BREAK

Barzilai, who called metformin a “tool” to open the door for aging-related FDA indications, said TAME and studies like it are going to change the way researchers look at some commonly used drugs.

“If you ask people to point out who around them may be aged 60 years or older, they’ll do a pretty good job,” Barzilai said. “Everyone knows there is a biology of aging. For some reason, they think they can’t do anything about it. That is a mistake. You can intervene in aging, even late in aging. Our lives are going to change when we have the regulatory pathway to do that.” – by Regina Schaffer